The long-term goals of this U19 Application are three fold: One, to study the human immune response to a vaccine in it's entirety; starting from the innate responses, to the peak effector T and B cell responses, to the development and maintenance of immunological memory. Two, to understand how a successful vaccine works and to use this knowledge for designing strategies for enhancing vaccine efficacy. Three, to understand the cellular basis of immune senescence and develop strategies for improving responses of the elderly to vaccination. Also, a major emphasis of this proposal is on using genomics and proteomics to define the molecular signatures of innate and adaptive responses after vaccination. In fact, our overarching hypothesis is that there will clearly be molecular and cellular signatures of "good" and "bad" vaccines and that identifying these signatures will allow us to manipulate the immune response to either enhance immunity in the case of vaccines and immune therapy, or to decrease it for autoimmunity, transplantation and gene therapy. To achieve our goals we have put together a highly interactive and integrated Application consisting of three research projects: 1. Immunological memory to vaccination (Ahmed and Lanzavecchia); 2. Modulating vaccine responses with dendritic cells and TLRs (Pulendran); and 3. Immune senescence (Goronzy). These research projects are closely tied to the Technical Development Components that consist of: 1. Molecular signatures of immune responses to vaccination (Aderem); 2. Human monoclonal antibodies to category A pathogens (Mittler); and 3. Development of novel T cell assays (Altman). This overall research effort will be supported by an Administrative/Statistical Core (Ahmed and Manatunga) and a Clinical Research Core (Feinberg). In addition, there is a program for the education and training of scientists who wish to do research in human immunology (Ansari) and a Review Committee for evaluating and funding high risk/high impact projects in human immunology.